WO1996007656A1 - Cis-hexahydro-5-(2-naphtalenyle)pyrrolo<3,4-c>pyrroles - Google Patents

Cis-hexahydro-5-(2-naphtalenyle)pyrrolo<3,4-c>pyrroles Download PDF

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Publication number
WO1996007656A1
WO1996007656A1 PCT/US1995/010373 US9510373W WO9607656A1 WO 1996007656 A1 WO1996007656 A1 WO 1996007656A1 US 9510373 W US9510373 W US 9510373W WO 9607656 A1 WO9607656 A1 WO 9607656A1
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cis
methyl
hydrogen
compound
hexahydro
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PCT/US1995/010373
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English (en)
Inventor
John M. Schaus
Robert D. Titus
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Eli Lilly And Company
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Priority to AU33268/95A priority Critical patent/AU3326895A/en
Publication of WO1996007656A1 publication Critical patent/WO1996007656A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • Reuptake inhibitors increase the levels of endogenous monoamines by inhibiting the neuronal mechanism for recovering the monoamine from the synapse without interfering with the neuronal receptors. If the reuptake inhibitor is selective for a particular monoamine, undesirable side-effects from the therapy can be reduced.
  • Fluoxetine a selective inhibitor of serotonin reuptake, has gained wide acceptance as a therapy for the treatment of depression and eating disorders, and is under active
  • tomoxetine hydrochloride (-)-N-methyl-3-(2- methylphenoxy) propanamine hydrochloride] is a selective inhibitor of norepinephrine uptake being investigated
  • the present invention provides novel serotonin reuptake inhibitors which are ring-substituted cis-hexahydro-5- (1,2,3,4-tetrahydro-2-naphthalenyl)pyrrolo- ⁇ 3,4-c>pyrroles of the formula
  • R is hydrogen, methyl or benzyl
  • R 1 is hydrogen or methyl
  • R 2 is selected from the group consisting of hydrogen, halo, C 1 -C 3 alkoxy, C 1 -C 3 alkylthio, C 1 -C 3 alkyl and hydroxy;
  • R 3 is selected from the group consisting of hydrogen and halo
  • R 4 is selected from the group consisting of hydrogen, halo, C 1 -C 3 alkoxy, C 1 -C 3 alkylthio, C 1 -C 3 alkyl and hydroxy;
  • R 5 is selected from the group consisting of hydrogen, halo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 acyl, fluoro- substituted C 1 -C 3 acyl, fluorosubstituted C 1 -C 3 alkyl, cyano, carboxamido, carboxyl and C 1 -C 3 hydroxyalkyl; all subject to the following provisos:
  • R 5 may be other than hydrogen only when R 2 is other than hydrogen
  • R 3 may be halo only when R 4 is other than hydrogen; and pharmaceutically acceptable acid addition salts thereof.
  • This invention also provides a pharmaceutical formulation which comprises, in association with a pharmaceutically acceptable carrier, diluent or excipient, a compound of
  • a further embodiment of the invention is a method for selectively inhibiting the reuptake of serotonin. More particularly, further embodiments are methods for treating a variety of disorders which have been linked to decreased neurotransmission of serotonin in mammals. Included among these disorders are depression, migraine pain, bulimia, premenstrual syndrome or late luteal phase syndrome,
  • C 1 -C 3 alkyl means a straight or branched alkyl chain bearing from one to three carbon atoms.
  • Such C 1 -C 3 alkyl groups are methyl, ethyl, propyl and isopropyl.
  • C 1 -C 3 alkoxy means any of methoxy, ethoxy, n- propoxy and isopropoxy.
  • halo means any of fluoro, chloro, bromo or iodo.
  • C 1 -C 3 acyl means any of formyl, acetyl and propionyl.
  • fluorosubstituted C 1 -C 3 acyl means mono-, di- or trifluorosubstituted acetyl, or mono-, di-, tri-, tetra- or pentafluorosubstituted propionyl. Specific examples are fluoroacetyl, trifluoroacetyl, ⁇ , ⁇ , ⁇ -trifluoropropionyl,- ⁇ fluoropropionyl, ⁇ , ⁇ -difluoropropionyl and the like.
  • fluorosubstituted C 1 -C 3 alkyl means mono-, di- or trifluoromethyl, or mono-, di-, tri-, tetra- or pentafluoroethyl, or mono-, di-, tri-, tetra-, penta-, hexa- or heptafluoropropyl or isopropyl.
  • C 1 -C 3 alkylthio means any of methylthio, ethylthio, n-propylthio and isopropylthio.
  • C 1 -C 3 hydroxyalkyl means a C 1 -C 3 alkyl having a hydroxyl group. Examples are hydroxymethyl, 2- hydroxyethyl, 3-hydroxypropyl and the like.
  • R 1 is preferably methyl, and when R 2 is other than hydrogen, R 1 preferably is hydrogen.
  • R 2 is other than hydrogen, it preferably is alkoxy or halo, and, more preferably, is methoxy or chloro. Most preferably, R 2 , when not hydrogen, is methoxy. It is also preferred that, when R 5 is other than hydrogen, it preferably is halo, and, most preferably, bromo.
  • R 4 is other than hydrogen, it preferably is halo, and, most preferably, chloro.
  • R 1 is hydrogen
  • the compounds of the present invention possess an asymmetric carbon labelled with an asterisk in the following formula:
  • each of the compounds exists as its individual d- and 1- stereoisomers as well as the racemic mixture of such isomers. Additionally, when R 1 is methyl, a second asymmetric carbon located at the carbon bearing the R ⁇ substituent is present, giving rise to a class of diastereomers.
  • the compounds of the present invention include not only the diastereomeric or dl-racemates but also their respective optically active diastereomers or d- and 1-isomers.
  • the invention includes pharmaceutically acceptable acid addition salts of the compounds defined by the above formula. Since the compounds of this invention are amines, they are basic in nature and accordingly react with any of a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. Since the free amines of the compounds of this invention are typically oils at room temperature, it is preferable to convert the free amines to their pharmaceutically acceptable acid addition salts for ease of handling and administration, since the latter are routinely solid at room temperature.
  • Acids commonly employed to form such salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids, such as p-toluene- sulfonic acid, methanesulfonic acid, oxalic acid, p-bromo- phenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like
  • organic acids such as p-toluene- sulfonic acid, methanesulfonic acid, oxalic acid, p-bromo- phenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like.
  • Examples of such pharmaceutically acceptable salts thus are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, mono- hydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propion- ate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, suc- cinate, suberate, sebacate, fumarate, maleate, butyne-1,4- dioate, hexyne-1, 6-dioate, benzoate, chlorobenzoate, methyl- benzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionat
  • compositions are those formed with hydrochloric acid, hydrobromic acid or maleic acid.
  • the maleic acid salts are most preferred.
  • the following compounds further illustrate compounds contemplated within the scope of this invention:
  • the compounds of the present invention may be prepared by procedures well known to those of ordinary skill in the art.
  • the compounds preferably are synthesized by preparation of selected 2-tetralones and cis-hexahydropyrrolo ⁇ 3,4-c>- pyrroles.
  • the 2-tetralone then is reductively aminated with a cis-hexahydropyrrolo ⁇ 3,4-opyrrole to produce selected compounds of this invention.
  • Other compounds of this invention are available by modifications of the ring
  • AM an optionally substituted cis-hexahydropyrrolo- ⁇ 3,4-c>pyrrole
  • R 2a halo, C 1 -C 3 alkoxy, C 1 -C 3 alkylthio or C 1 -C 3 alkyl.
  • R 2a halo, al x lk l i
  • the tetralones represent the intermediates which, when reductively aminated with the appropriate cis-hexahydropyrrolo ⁇ 3,4-c>pyrrole, result in compounds of this invention or compounds that have the core structure of the compounds of this invention.
  • tetralones are available by any of a wide range of recognized methods. For example, they can be produced by a Friedel-Crafts reaction of an appropriately ring-substituted phenylacetyl chloride with ethylene in the presence of aluminum chloride.
  • a 1,7-dialkoxynaphthalene can be reduced with sodium and the resultant enol ether hydrolyzed to the corresponding monoalkoxytetralone.
  • Another method for obtaining a specific tetralone is via 1,4-dialkoxynaphthalene.
  • the naphthalene is reduced with sodium to give 1,4-dihydro-5,8-dialkoxynaphthalene, and the latter is oxidized with m-chloroperbenzoic acid to the corresponding epoxide.
  • the epoxide is reduced with lithium aluminum hydride (LAH), and the resulting alcohol oxidized to the desired tetralone using pyridinium chlorochromate.
  • LAH lithium aluminum hydride
  • the methyl-substituted tetralone can be prepared from the unsubstituted tetralone.
  • the tetralone is first treated with pyrrolidine to produce the corresponding 1,2-dihydro-3- pyrrolidinylnaphthalene.
  • the latter upon treatment with iodomethane followed by acid hydrolysis, gives the desired 1- methyl-2-tetralone.
  • the 2-methyl- and 2-benzyl-cis-hexahydropyrrolo ⁇ 3,4-c>- pyrroles are conveniently prepared by the condensation of the appropriately N-substituted glycine with paraformaldehyde which immediately undergoes a cycloaddition with dimethyl maleate to give the corresponding N-substituted-cis-3,4- pyrrolidinedicarboxylic acid dimethyl ester.
  • the diester is reduced with lithium aluminum hydride to the corresponding diol which is then converted to the dimesylate by reaction with methanesulfonyl chloride in the presence of
  • the dimesylate can be reacted with benzylamine at reflux to give cis-hexahydro-2-methyl-5- benzylpyrrolo ⁇ 3,4-c>pyrrole, followed by debenzylation under catalytic hydrogenation conditions employing 10% palladium on carbon, giving cis-hexahydro-2-methylpyrrolo- ⁇ 3,4-c>pyrrole.
  • the dimesylate can be reacted with anhydrous ammonia in methanol at 200°C in a pressure vessel to give the same compound.
  • the tetralone can be converted to a compound of this invention or to one useful as an intermediate to a compound of this invention by reductive amination with a cis- hexahydropyrrolo ⁇ 3,4-c>pyrrole.
  • the tetralone is first reacted with a cis-hexahydropyrrolo ⁇ 3,4-c>pyrrole to form the corresponding enamine which is then reduced with sodium borohydride to the tetrahydronaphthalene.
  • a tetrahydronaphthalene having a bromo substituent, whether in the 5-, 6- or 8-position, is useful to produce other compounds of this invention via formation of the corresponding organolithium using n-butyllithium.
  • the reactive organolithium intermediate can be trapped with a wide variety of electrophiles to produce compounds of this invention.
  • treatment of the organolithium with a dialkyl disulfide produces an alkylthio substituent, with FOClO 2 a fluoro substituent, with N-chlorosuccinimide a chloro substituent, with iodine an iodo substituent, with N,N-dimethylformamide or an acyl anhydride an acyl
  • the 5-bromotetrahydronaphthalene is converted to its corresponding cyano compound by treatment with cuprous cyanide at elevated temperature.
  • substituent is hydroxy are available from the corresponding alkoxy compound by treatment with 48% hydrobromic acid or trimethylsilyl iodide.
  • optically active isomers of the racemates of this invention are also considered part of this invention.
  • Such optically active isomers may be prepared from their
  • the pharmaceutically acceptable acid addition salts of the invention are typically formed by reacting a cis- hexahydro-5-(1,2,3,4-tetrahydro-2-naphthalenyl)pyrrolo- ⁇ 3,4-c>pyrrole of this invention with an equimolar or excess amount of acid.
  • the reactants are generally combined in a mutual solvent such as ethanol, and the salt normally precipitates out of solution within about 1 hour to 10 days, and can be isolated by filtration.
  • NMR data appearing in the following examples refers to the free bases of the subject compounds.
  • reaction mixture was stirred for 15 minutes at 0°C and then for 1.5 hours at ambient. The reaction mixture was then quenched with dilute aqueous sodium hydroxide solution and then was extracted with dichloromethane. The organic phase was dried over sodium sulfate and then concentrated in vacuo to give 9.6 gm of the desired compound as an orange oil.
  • the title compound was prepared by adding 100 mL liquid ammonia to a solution of 1.02 gm (3.3 mMol) N-methyl-cis-3,4-di(methanesulfonyloxymethyl)- pyrrolidine in 100 mL methanol and the mixture was heated in a sealed reactor at 200°C for 5 hours. The reaction mixture was then concentrated in vacuo to give a tan solid. This solid was dissolved in water and the solution made basic with aqueous sodium hydroxide solution. The aqueous phase was then extracted with 3:1 chloroform: isopropanol and the organic phase dried over sodium sulfate then concentrated in vacuo to give 0.243 gm of the desired product as an orange oil.
  • reaction mixture was quenched with 10% hydrochloric acid, filtered through a pad of Celite and the filtrate extracted with methylene chloride.
  • the remaining aqueous phase was made basic with aqueous sodium hydroxide and extracted with 3:1 chloroform: isopropanol .
  • the organic phase was dried over sodium sulfate and concentrated in vacuo to give 0.204 gm of an orange oil.
  • reaction mixture was then poured into ice, made basic with concentrated ammonium hydroxide and extracted with dichloromethane. The organic phase was dried over sodium sulfate and then concentrated in vacuo to give a yellow glass. The glass was dissolved in dichloromethane and then placed on a flash silica gel column. The column was eluted with 97:3 dichloromethane:methanol containing a trace of ammonium hydroxide. Fractions containing the desired
  • reaction mixture was then stirred at reflux under nitrogen with azeotropic removal of water. After 4 hours the reaction mixture was cooled to ambient and then concentrated in vacuo to give a yellow solid. To a solution of this yellow solid in 25 mL of ethanol were added in portions 0.40 gm (10.5 mMol) sodium borohydride and the reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was then diluted with 10% hydrochloric acid and extracted once with diethyl ether. The phases were separated and the aqueous phase was made basic with concentrated ammonium hydroxide. This aqueous phase was extracted with dichloromethane and the organic phase dried over sodium sulfate then concentrated in vacuo to a brown oil.
  • the oil was dissolved in 25 mL of p-dioxane. To the solution then were added 7.5 mL of methyl iodide and the mixture was stirred for 18 hours at reflux under nitrogen. The mixture then was diluted with 25 mL of water and 1 mL of glacial acetic acid, after which it was stirred at reflux for 3 hours. The mixture then was cooled to room temperature and the volatiles removed in vacuo. The resulting residue was suspended in water and then extracted with diethyl ether. The organic extracts were combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated in vacuo to give 3.5 gm of a dark oil. The oil was dissolved in 1:1 hexane:diethyl ether and placed on a flash silica column. The column was eluted with 1:1
  • the compounds of this invention are useful for selectively inhibiting the reuptake of
  • another embodiment of this invention is a method for inhibiting serotonin reuptake in mammals which comprises administering to a mammal requiring increased serotonin neurotransmission a pharmaceutically effective amount of the invention.
  • pharmaceutically effective amount represents an amount of a compound of the invention which is capable of inhibiting serotonin reuptake.
  • the specific dose of compound administered according to this invention will be determined by the particular circumstances surrounding the case including, for example, the compound administered, the route of administration and the condition being treated.
  • a typical dose will generally be in the range of about 0.01 mg/kg to about 20 mg/kg of the active compound of this invention.
  • Preferred daily doses will generally be in the range of about 0.05 mg/kg to about 10 mg/kg, and ideally from about 0.1 mg/kg to 5 mg/kg.
  • the compounds of this invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal.
  • routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal.
  • a special feature of the compounds of this invention is that they are selective as inhibitors of serotonin reuptake relative to other monoamines.
  • a variety of physiologic functions have been shown to be subject to influence by brain serotonergic neural systems. As such, the compounds of this invention are believed to have the ability to treat in mammals a variety of disorders associated with these neural systems such as eating
  • the present invention also provides methods of treating the above disorders at rates set forth above for inhibiting serotonin reuptake in mammals.
  • 3 H-serotonin 3 H-5-hydroxy- tryptamine, 3 H-5HT
  • Cortical synaptosomes (equivalent to 1 mg protein) were incubated at 37°C for 5 min. in 1 mL of Krebs-bicarbonate medium
  • Table I The results of the evaluation of various compounds of the present invention are set forth below in Table I.
  • the first column provides the Example Number of the compound evaluated; the next 4 columns identify the structure of the compound evaluated when taken with the formula set forth in the heading and the final column provides the amount of the test compound expressed in nanomolar concentration needed to inhibit the uptake of 3 H-5HT by 50% and is
  • the compounds of this invention are preferably
  • another embodiment of the present invention is a pharmaceutical formulation comprising a compound of the invention and a pharmaceutically acceptable carrier, diluent or excipient therefor.
  • the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container.
  • a carrier which may be in the form of a capsule, sachet, paper or other container.
  • the carrier serves as a diluent, it may be a solid, semisolid or liquid material which acts as a vehicle, excipient or medium for the active ingredient.
  • the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatine capsules, suppositories, sterile injectable solutions, sterile packaged powders and the like.
  • Suitable carriers, excipients and diluents are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth,
  • gelatin calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl
  • compositions of the invention may be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • the compositions are preferably formulated in a unit dosage form, each dosage generally containing from about 0.1 to about 500 mg, and preferably from about 1 to about 250 mg, of the active ingredient.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier.
  • Hard gelatine capsules are prepared using the following ingredients:
  • the above ingredients are mixed and filled into hard gelatine capsules in 460 mg quantities.
  • a tablet is prepared using the ingredients below:
  • the components are blended and compressed to form tablets each weighing 665 mg.
  • An aerosol solution is prepared containing the following components:
  • the active compound is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to -30°C and trnsferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remaineder of the propellant. The valve units are then fitted to the container.
  • Tablets each containing 60 mg of active ingredient are made as follows:
  • the active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly.
  • the aqueous solution containing polyvinylpyrrolidone is mixed with the resultant powder, and the mixture is then passed through a No. 14 mesh U.S. sieve.
  • the granules so produced are dried at 50°C and passed through a No. 18 mesh U.S.
  • Capsules each containing 80 mg of active ingredient, are made as follows:
  • the active ingredient, cellulose, starch and magnesium stearate are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatine capsules in 200 mg quantities.
  • Suppositories each containing 225 mg of active ingredient, are made as follows:
  • Suspensions each containing 50 mg of active ingredients per 5 mL dose, are made as follows:
  • the active ingredient is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste.
  • the benzoic acid solution, flavor and color are diluted with a portion of the water and added with stirring. Sufficient water is then added to produce the required volume.
  • An intravenous formulation may be prepared as follows

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)

Abstract

La présente invention a pour objet des cis-hexahydro-5-(1,2,3,4-tétrahydro-2-naphtalényle)pyrrolo<3,4-c>pyrroles à substitution de cycle, lesquels constituent des inhibiteurs sélectifs du recaptage de la sérotonine.
PCT/US1995/010373 1994-09-02 1995-08-14 Cis-hexahydro-5-(2-naphtalenyle)pyrrolo<3,4-c>pyrroles WO1996007656A1 (fr)

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AU33268/95A AU3326895A (en) 1994-09-02 1995-08-14 Cis-hexahydro-5-(2-naphthalenyl)pyrrolo(3,4-c)pyrroles

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US08/300,299 US5457121A (en) 1994-09-02 1994-09-02 Cis-hexahydro-5-(1,2,3,4-tetrahydro-2-naphthalenyl)pyrrolo<3,4-c>pyrroles as inhibitors of serotonin reuptake
US08/300,299 1994-09-02

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Cited By (7)

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EP0721777A2 (fr) * 1995-01-11 1996-07-17 Eli Lilly And Company Utilisation de tomoxetine pour le traitement de l'hyperactivité induite par les troubles d'attention
WO2001044243A2 (fr) * 1999-12-14 2001-06-21 Neurosearch A/S Nouveaux heteroaryles-diazabicycloalcanes
US7144914B2 (en) 2001-02-02 2006-12-05 Astrazeneca Ab 3,7-diazabicyclo[3.3.0]octanes and their use in the treatment of cardiac arrhythmias
US7164019B2 (en) 2004-06-09 2007-01-16 Roche Palo Alto Llc Heterocyclic antiviral compounds
US7665658B2 (en) 2005-06-07 2010-02-23 First Data Corporation Dynamic aggregation of payment transactions
EP2284171A1 (fr) 2006-11-02 2011-02-16 Targacept, Inc. Amides de diazabicycloalkanes sélectifs pour sous-types du récepteur de l'acétylcholine nicotinique
JP2022535037A (ja) * 2019-05-30 2022-08-04 シャンハイ インスティテュート オブ マテリア メディカ、チャイニーズ アカデミー オブ サイエンシーズ 縮合環化合物、その製造方法及び用途

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US5525347A (en) * 1995-01-31 1996-06-11 Medical University Of South Carolina Composition and methods for treating performance anxiety
DK1225881T3 (da) 1999-09-03 2006-06-12 Apbi Holdings Llc Anvendelsen af dapoxetin, en hurtigt-virkende selektiv serotonin genoptagelseshæmmer, til behandling af seksuel dysfunktion

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0721777A2 (fr) * 1995-01-11 1996-07-17 Eli Lilly And Company Utilisation de tomoxetine pour le traitement de l'hyperactivité induite par les troubles d'attention
EP0721777A3 (fr) * 1995-01-11 1997-03-05 Lilly Co Eli Utilisation de tomoxetine pour le traitement de l'hyperactivité induite par les troubles d'attention
WO2001044243A2 (fr) * 1999-12-14 2001-06-21 Neurosearch A/S Nouveaux heteroaryles-diazabicycloalcanes
WO2001044243A3 (fr) * 1999-12-14 2002-10-31 Neurosearch As Nouveaux heteroaryles-diazabicycloalcanes
US6815438B2 (en) 1999-12-14 2004-11-09 Neurosearch A/S Heteroaryl-diazabicycloalkanes
US7144914B2 (en) 2001-02-02 2006-12-05 Astrazeneca Ab 3,7-diazabicyclo[3.3.0]octanes and their use in the treatment of cardiac arrhythmias
US7714018B2 (en) 2004-06-09 2010-05-11 Roche Palo Alto Llc Heterocyclic antiviral compounds
US7164019B2 (en) 2004-06-09 2007-01-16 Roche Palo Alto Llc Heterocyclic antiviral compounds
US7665658B2 (en) 2005-06-07 2010-02-23 First Data Corporation Dynamic aggregation of payment transactions
EP2284171A1 (fr) 2006-11-02 2011-02-16 Targacept, Inc. Amides de diazabicycloalkanes sélectifs pour sous-types du récepteur de l'acétylcholine nicotinique
US8114889B2 (en) 2006-11-02 2012-02-14 Targacept, Inc. Nicotinic acetylcholine receptor sub-type selective amides of diazabicycloalkanes
US8268860B2 (en) 2006-11-02 2012-09-18 Targacept, Inc. Sub-type selective amides of diazabicycloalkanes
US8859609B2 (en) 2006-11-02 2014-10-14 Targacept, Inc. Nicotinic acetylcholine receptor sub-type selective amides of diazabicycloalkanes
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JP2022535037A (ja) * 2019-05-30 2022-08-04 シャンハイ インスティテュート オブ マテリア メディカ、チャイニーズ アカデミー オブ サイエンシーズ 縮合環化合物、その製造方法及び用途

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